Oral budesonide for treatment of people with active ulcerative colitis

What is ulcerative colitis?

Ulcerative colitis is a debilitating long-term (chronic), inflammatory bowel disease that affects the large bowel. When people with ulcerative colitis are experiencing symptoms which may include bleeding, diarrhoea and abdominal pain, the disease is said to be 'active'; periods when the symptoms stop are called 'remission'. A common initial treatment of ulcerative colitis is oral steroid therapy. Unfortunately, conventional steroids are usually absorbed into the body and cause significant unwanted side-effects. These may include but are not limited to weight gain, diabetes, growth retardation, acne, mood instability, and high blood pressure.

What is budesonide?

Budesonide is a steroid that is quickly metabolised by the liver thereby reducing corticosteroid-related side-effects. There are currently three formulations of budesonide: two standard capsules both designed to release the drug in the outer part of the small intestine and right colon; and the newer Budesonide-MMX® capsule designed to release the drug throughout the entire colon.

What did the researchers investigate?

The researchers investigated whether budesonide (both standard budesonide and a new specialised formulation called budesonide-MMX®) produces remission in people with active ulcerative colitis; and whether these medications cause any harm (side-effects). The researchers searched the medical literature up to April 28, 2015.

What did the researchers find?

We found six studies that included a total of 1808 participants. One study (343 participants) compared standard budesonide to mesalamine (an anti-inflammatory drug composed of 5-aminosalicylic acid), one study (72 participants) compared standard budesonide to conventional corticosteroids, four studies (1393 participants) compared budesonide-MMX® to placebo (a fake medicine with no active ingredients such as a sugar pill) or active comparators including Entocort (standard budesonide), prednisolone (a conventional steroid drug) or mesalamine. Four studies were judged to be of high quality and two studies were judged to be of low quality.

Evidence from three studies including 900 participants indicates that the newer formulation, budesonide-MMX® at a dose of 9 mg/day was superior to placebo for induction of remission irrespective of mesalamine use. There is evidence to suggest that budesonide-MMX® at a dose of 9 mg/day is particularly effective in patients with left-sided disease as opposed to patients with more extensive disease. One small study (32 participants) comparing standard budesonide to placebo found no difference in remission rates. Evidence from one study (343 participants) comparing standard budesonide to mesalamine suggests that standard budesonide was significantly less effective than mesalamine for induction of remission. However, another study (247 participants) found no difference in remission rates between patients treated with budesonide-MMX® and mesalamine. One study (212 participants) found no difference in remission rates between patients treated with budesonide-MMX® 9 mg/day and standard budesonide 9 mg/day. One small study (72 participants) found no difference in endoscopic remission rates between patients treated with standard budesonide and prednisolone, however budesonide patients were less likely than prednisolone patients to experience adrenal suppression, a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. Commonly reported side-effects in the studies include worsening ulcerative colitis, headache, pyrexia (raised body temperature), insomnia (difficulty sleeping), back pain, nausea, abdominal pain, diarrhoea, flatulence and nasopharyngitis (common cold). More studies with larger numbers of participants are needed to allow conclusions regarding the comparative effectiveness of budesonide versus conventional steroid drugs, budesonide-MMX® versus standard budesonide and budesonide versus mesalamine.

Authors' conclusions:

Moderate quality evidence to supports the use of oral budesonide-MMX® at a 9 mg daily dose for induction of remission in active ulcerative colitis, particularly in patients with left-sided colitis. Budesonide-MMX® 9 mg daily is effective for induction of remission in the presence or absence of concurrent 5-ASA therapy. Further, budesonide-MMX® appears to be safe, and does not lead to significant impairment of adrenocorticoid function compared to placebo. Moderate quality evidence from a single study suggests that mesalamine may be superior to standard budesonide for the treatment of active ulcerative colitis. Low quality evidence from one study found no difference in remission rates between budesonide MMX® and mesalamine. Very low quality evidence from one small study showed no difference in endoscopic remission rates between standard budesonide and prednisolone. Low quality evidence from one study showed no difference in remission rates between budesonide-MMX® and standard budesonide. Adequately powered studies are needed to allow conclusions regarding the comparative efficacy and safety of budesonide versus prednisolone, budesonide-MMX® versus standard budesonide and budesonide versus mesalamine.

Read the full abstract...

Background:

Corticosteroids are first-line therapy for induction of remission in ulcerative colitis. Although corticosteroids may improve symptoms, they have significant adverse effects. Steroids which act topically, with less systemic side-effects may be more desirable. Budesonide is a topically acting corticosteroid with extensive first pass hepatic metabolism. There are currently three formulations of budesonide: two standard formulations including a controlled-ileal release capsule and a pH-dependent capsule both designed to release the drug in the distal small intestine and right colon; and the newer Budesonide-MMX® capsule designed to release the drug throughout the entire colon.

Objectives:

The primary objective was to evaluate the efficacy and safety of oral budesonide for the induction of remission in ulcerative colitis.

Search strategy:

We searched MEDLINE, EMBASE, CENTRAL, and the Cochrane IBD Group Specialised Register from inception to April 2015. We also searched reference lists of articles, conference proceedings and ClinicalTrials.gov.

Selection criteria:

Randomised controlled trials comparing oral budesonide to placebo or another active therapy for induction of remission in ulcerative colitis were considered eligible. There were no exclusions based on patient age or the type, dose, duration or formulation of budesonide therapy.

Data collection and analysis:

Two independent investigators reviewed studies for eligibility, extracted data and assessed study quality. Methodological quality was assessed using the Cochrane risk of bias tool. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. The primary outcome was induction of remission (as defined by the primary studies) at week eight. Secondary outcomes included clinical, endoscopic and histologic improvement, adverse events and early withdrawal. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for each dichotomousoutcome and the mean difference (MD) and corresponding 95% CI for each continuous outcome. Data were analysed on an intention-to-treat basis.

Main results:

Six studies (1808 participants) were included. Four studies compared budesonide-MMX® with placebo, one small pilot study looked at clinical remission at week four, and was subsequently followed by three large, studies that assessed combined clinical and endoscopic remission at week eight. Although two placebo-controlled studies had mesalamine and Entocort (standard budesonide) treatment arms, these studies were not sufficiently powered to compare Budesonide-MMX® with these active comparators. One small study compared standard budesonide with prednisolone and one study compared standard budesonide to mesalamine. Four studies were rated as low risk of bias and two studies had an unclear risk of bias. A pooled analysis of three studies (900 participants) showed that budesonide-MMX® 9 mg was significantly superior to placebo for inducing remission (combined clinical and endoscopic remission) at 8 weeks. Fifteen per cent (71/462) of budesonide-MMX® 9 mg patients achieved remission compared to 7% (30/438) of placebo patients (RR 2.25, 95% CI 1.50 to 3.39). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (101 events). A subgroupanalysis by concurrent mesalamine use suggests higher efficacy in the 442 patients who were not considered to be mesalamine-refractory (RR 2.89, 95% CI 1.59 to 5.25). A subgroupanalysis by disease location suggests budesonide is most effective in patients with left-sided disease (RR 2.98, 95% CI 1.56 to 5.67; 289 patients). A small pilot study reported no statistically significant difference in endoscopic remission between budesonide and prednisolone (RR 0.75, 95% CI 0.23 to 2.42; 72 patients). GRADE indicated that the overall quality of the evidence supporting this outcome was very low due to unclear risk of bias and very sparse data (10 events). Standard oral budesonide was significantly less likely to induce clinical remission than oral mesalamine after 8 weeks of therapy (RR 0.72, 95% CI 0.57 to 0.91; 1 study, 343 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (161 events). Another study found no difference in remission rates between budesonide-MMX® 9 mg and mesalamine (RR 1.48, 95% CI 0.81 to 2.71; 247 patients). GRADE indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (37 events). One study found no difference in remission rates between budesonide-MMX® 9 mg and standard budesonide 9 mg (RR 1.38, 95% CI 0.72 to 2.65; 212 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (32 events). Suppression of plasma cortisol was more common in prednisolone-treated patients (RR 0.02, 95% CI 0.0 to 0.33). While budesonide does appear to suppress morning cortisol to some extent, mean morning cortisol values remained within the normal range in 2 large studies (n = 899) and there was no difference in glucocorticoid-related side-effects across different treatment groups. Further, study withdrawal due to adverse events was not more common in budesonide compared with placebo treated patients (RR 0.85, 95% CI 0.53 to 1.38). Common adverse events included worsening ulcerative colitis, headache, pyrexia, insomnia, back pain, nausea, abdominal pain, diarrhoea, flatulence and nasopharyngitis.

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